Therapeutic Strategies Targeting Cancer Stem cell. (original) (raw)
Common stemness regulators of embryonic and cancer stem cells
World journal of stem cells, 2015
Pluripotency of embryonic stem cells (ESCs) and induced pluripotent stem cells is regulated by a well characterized gene transcription circuitry. The circuitry is assembled by ESC specific transcription factors, signal transducing molecules and epigenetic regulators. Growing understanding of stem-like cells, albeit of more complex phenotypes, present in tumors (cancer stem cells), provides a common conceptual and research framework for basic and applied stem cell biology. In this review, we highlight current results on biomarkers, gene signatures, signaling pathways and epigenetic regulators that are common in embryonic and cancer stem cells. We discuss their role in determining the cell phenotype and finally, their potential use to design next generation biological and pharmaceutical approaches for regenerative medicine and cancer therapies.
The commonality of plasticity underlying multipotent tumor cells and embryonic stem cells
Journal of Cellular Biochemistry, 2007
Aggressive cancer cells and pluripotent stem cells converge in their capacity for self-renewal, proliferation and plasticity. Recent studies have capitalized on these similarities by demonstrating that tumors arise from specific cancer stem cell populations that, in a manner reminiscent of normal stem cells, are able to both self-renew and give rise to a heterogeneous tumor population. This stem cell like function of aggressive cancer cells is likely attributable to the ectopic expression of embryonic factors such as Nodal and Cancer Testis Specific Antigens (CTAs), which maintain a functional plasticity by promoting pluripotency and immortality. During development, the expression of these embryonic factors is tightly regulated by a dynamic array of mediators, including the spatial and temporal expression of inhibitors such as Lefty, and the epigenetic modulation of the genome. In aggressive cancer cells, particularly melanoma, this balance of regulatory mediators is disrupted, leading to the aberrant expression of pluripotency-associated genes. By exposing aggressive cancer cells to embryonic microenvironments, this balance of regulatory mediators is restored, thereby reprogramming tumor cells to a more benign phenotype. These stem cell-derived mediators, as well as the genes they regulate, provide therapeutic targets designed to specifically differentiate and eradicate aggressive cancers.
T h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 355;12 www.nejm.
Markers in normal and cancer stem cells
Cancer Biomarkers, 2007
In an effort to better understand and address the challenges of cancer research and treatment, a new model of tumorigenesis is being developed-the cancer stem cell model. Building upon traditionl concepts of cancer and stem cells, this model is intended to shed new light on the continued struggle with treatment issues such as tumor drug-resistance and recurrence. This review describes the cancer stem cell model with an emphasis on markers that represent the "stemness" phenotype. A thorough understanding of normal and cancer stem cells is necessary for a prescise delineation of cancer stem cells. The objective of such an improved delineation is to develop targeted therapy for selective elimination of cancer stem cells with minimal toxicity to normal stem cells. Specific targeting of cancer stem cells has proved to be a significant challenge due to the commonality of many markers between normal and cancer stem cells. However, research in the area of cancer biomarkers is slowly, but steadily, progressing.
The Cancer Stem Cell Hypothesis: A Guide to Potential Molecular Targets
Cancer Investigation, 2014
Common cancer theories hold that tumor is an uncontrolled somatic cell proliferation caused by the progressive addition of random mutations in critical genes that control cell growth. Nevertheless, various contradictions related to the mutation theory have been reported previously. These events may be elucidated by the persistence of residual tumor cells, called Cancer Stem Cells (CSCs) responsible for tumorigenesis, tumor maintenance, tumor spread, and tumor relapse. Herein, we summarize the current understanding of CSCs, with a focus on the possibility to identify specific markers of CSCs, and discuss the clinical application of targeting CSCs for cancer treatment.
Pluripotency and differentiation in embryos and stem cells
The International journal of developmental biology, 2008
Each year many scientific meetings are held on stem cells to appraise the state of knowledge on their potency, differentiation and applications. So why did we hold another meeting? Because we thought one aspect was not adequately addressed in the others. When thinking of how our body is derived from a single fertilized egg, it is self-evident that the embryo is the 'mother' of all stem cells. This fact is probably overlooked because it is so remote (decades back in our lives!) and because embryonic stem cells do not exist as such in the embryo. However, this also tends to be ignored on purpose in many stem cell meetings because working on (human) embryos brings up substantial ethical concerns that bear on the scientific undertaking like nothing else. The origin of stem cells has become even more of a sensitive issue since the discovery in 2006 that embryonic stem (ES) cell-like cells can be generated in a Petri dish straight from somatic cells by retrovirus-mediated transfer of selected genes. These new cells have been named 'induced pluripotent stem' (iPS) cells and have been obtained without any egg or embryo consumption (Takahashi and Yamanaka, 2006). This leads to the first topic of our meeting: natural and induced pluripotency. Many stem cells, irrespective of their origin (adult, fetal, embryonic, induced), almost invariably grow in vitro as multicellular structures referred to as 'colonies' to secure their potency. From an ontogenic perspective, the first 'colony' is arguably the morula-stage embryo with its 8-16 cells. Despite the fact that access to embryos is inherently difficult, more about cell fate control appears to be known in embryos than in stem cells. This leads to the second topic of our meeting: mechanisms of cell fate control. Stem cells can be propagated for many cell doublings and can give rise to a wide range of cell types found in the body. This makes them excellent candidates for cell-and tissue-replacement therapies. However, there is a general sense that the more potent stem cells are, the more likely they are to deviate from the normal physiological path of their differentiation, and that they may give rise to tumours. This leads to the third and last topic of our meeting: adult and cancer stem cells. The Pavia meeting took place on January 17 th and 18 th 2008 inside the beautiful, frescoed halls of Collegio Ghislieri and
Stem Cells, 2009
Human germ cell tumors are often metastatic, presumably due to distal site tumor growth by cancer stem cells. To determine whether cancer stem cells can be identified in a transplantation model of testicular germ cell tumor, we transplanted murine embryonic germ cells (EGCs) into the testis of adult severe combined immunodeficient mice. Transplantation resulted in a locally invasive solid tumor, with a cellular component that generated secondary tumors upon serial transplantation. The secondary tumors were invariably metastatic, a feature not observed in the primary tumors derived from EGCs. To characterize the differences between EGCs and the tumor-derived stem cells, we performed karyotype and microarray analysis. Our results show that generation of cancer stem cells is associated with the acquisition of nonclonal genomic rearrangements not found in the originating population. Furthermore, pretreatment of EGCs with a potent inhibitor of self-renewal, retinoic acid, prevented tumor formation and the emergence of these genetically unstable cancer stem cells. Microarray analysis revealed that EGCs and first- and second-generation cancer stem cells were highly similar; however, approximately 1,000 differentially expressed transcripts could be identified corresponding to alterations in oncogenes and genes associated with motility and development. Combined, the data suggest that the activation of oncogenic pathways in a cellular background of genetic instability, coupled with an inherent ability to self-renew, is involved in the acquisition of metastatic behavior in the cancer stem cell population of tumors derived from pluripotent cells. STEM CELLS2009;27:18–28
Cancer stem cells: an old ideaa paradigm shift
Cancer research, 2006
Although the concept that cancers arise from ''stem cells'' or ''germ cells'' was first proposed about 150 years ago, it is only recently that advances in stem cell biology have given new impetus to the ''cancer stem cell hypothesis.'' Two important related concepts of this hypothesis are that (a) tumors originate in either tissue stem cells or their immediate progeny through dysregulation of the normally tightly regulated process of self-renewal. As a result of this, (b) tumors contain a cellular subcomponent that retains key stem cell properties. These properties include self-renewal, which drives tumorigenesis, and differentiation albeit aberrant that contributes to cellular heterogeneity. Recent experimental evidence in a variety of tumors has lent strong support to the cancer stem cell hypothesis that represents a paradigm shift in our understanding of carcinogenesis and tumor cell biology. This hypothesis has fundamental implications for cancer risk assessment, early detection, prognostication, and prevention. Furthermore, the current development of cancer therapeutics based on tumor regression may have produced agents that kill differentiated tumor cells while sparing the rare cancer stem cell population. The development of more effective cancer therapies may thus require targeting this important cell population.